Hypoxia-dependent mechanisms in the pulmonary circulation : Role of dimethylarginine dimethylaminohydrolase 1 (DDAH-1) in acute, sustained and chronic hypoxia
Hypoxia is a prominent factor for induction of pulmonary vasoconstriction and pulmonaryhypertension (PH). Hypoxic pulmonary vasoconstriction (HPV) can be induced by alveolarhypoxia lasting seconds to minutes (= acute HPV) or minutes to hours (= sustained HPV).Both phases of HPV play an important role in matching local perfusion to ventilation, thusoptimizing pulmonary gas exchange. However, the irreversible increase of pulmonary arterialpressure (PAP) induced by sustained HPV might also facilitate development of PH. PH is afatal disease characterized by increased pulmonary vascular resistance. The pathophysiologyof PH can include endothelial dysfunction and pulmonary arterial smooth muscle cellhypertrophy and proliferation. Nitric oxide (NO) is a well-known vasodilator controlling adiverse range of pulmonary functions such as regulation of PAP. Asymmetric omega - NG, NG-dimethylarginine (ADMA) is a potent inhibitor of all three nitric oxide synthase (NOS)isoforms, resulting in impaired NO production. ADMA is degraded by dimethylargininedimethylaminohydrolase (DDAH) 1 and 2, both expressed in the lung.Therefore, the current study investigated the effects of DDAH1 on acute and sustained HPVas well as on hypoxia-induced PH in isolated, ventilated and perfused mouse lungs, and in awhole animal model. PH was quantified by measurement of right ventricular systolicpressure, right-to-left heart ratio and vascular morphometry. Concentration of ADMA andcyclic 3´, 5´-guanosine monophophate (cGMP) was determined by enzyme linkedimmunosorbent assay (ELISA). NO was measured by a chemiluminescence analyzer.DDAH1 overexpression had no effects on acute HPV. However, in sustained HPV (3 hours ofhypoxia), DDAH1 overexpression abolished the increase in PAP almost completely andconcomitantly decreased levels of ADMA, and significantly increased levels of NO andcGMP compared to wild-type (WT) mice. Sustained HPV could be restored by application ofthe NOS inhibitor N omega -Nitro-L-arginine (L-NNA), and the soluble guanylyl cyclase (sGC)inhibitor 1H-[1, 2, 4]oxadiazolo-[4, 3-a]quinoxalin-1-one (ODQ). Chronic hypoxic exposure(10% O2, 3 weeks) induced PH in WT and DDAH1tg mice without a difference in the degreeof PH in both mouse strains.This study revealed, that DDAH1 regulates ADMA concentration, NO bioavailability andvessel tone specifically in sustained HPV. Therefore, getting insight into DDAH1-dependentmechanisms may help find new strategies for treatment of diseases with impaired ventilationperfusionmatching due to decreased sustained HPV.
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